Malaria remains one of most significant infectious diseases world-wide. Through its impact on human fitness, the malaria parasite has had a substantial influence upon the genetic constitution of its host. The proposed research will examine the genetic variability which has arisen under this intense selective pressure and assess the impact of this variability on clinical malaria outcomes. The specific aims of this project are: (1) to assess the impact of host genetic polymorphisms on the incidence of uncomplicated malaria In Kampala, Uganda; (2) to assess the impact of host genetic polymorphisms on the response to antimalarial therapy in Uganda; (3) to identify host polymorphisms that impact upon the development of cultured malaria parasites. The studies designed to achieve these aims will utilize molecular techniques to evaluate polymorphisms in subjects from multiple completed and ongoing studies of antimalarial drug efficacy conducted in Uganda. They will also use cultured malaria parasites to evaluate the in vitro impacts of polymorphisms in human erythrocytes. Findings from these studies will contribute to the understanding of malaria pathogenesis. Additionally, the identification of natural host defenses against this parasite will aid in drug discovery, and assist in the design of drug and vaccine trials. The applicant, Dr. Sunil Parikh, is an infectious disease specialist with a strong commitment to malaria research and international health. This project is intended to provide him with in-depth training in translational clinical malaria research, molecular genetics, epidemiology, and biostatistics. Mentoring will be provided by senior investigators with overlapping expertise in clinical research, molecular parasitology, and epidemiology. With the skills gained from this project, Dr. Parikh will be able to utilize modern molecular epidemiology techniques to investigate human genetic factors underlying susceptibility to malaria and he will be well equipped for a career in academic research.